Synergy of the innate and acquired immune responses in tumor immunology

描述（由申请人提供）：TLR和CD40激动剂与肿瘤抗原联合使用是一种新的疫苗平台，可引起强大的免疫力，从而有效根除预先存在的癌症。CD40和TLR激动剂（TLR*）联合使用的协同作用表现为肿瘤效应T细胞的频率大大提高。将寻求最大化这种方法以提供更好的癌症治疗保护，了解肿瘤特异性效应T细胞产生的机制，并在多种临床相关的黑色素瘤模型中测试这种疫苗平台方法（Specific Aim#1）。虽然了解一种有效的癌症疫苗如何引发强效的肿瘤效应T细胞很重要，但解决它如何限制调节性T细胞（Treg）的出现也同样重要。大量证据表明，天然(n)Treg和适应性(a)Treg可以显著影响对肿瘤的免疫反应。我们的数据表明，只有同时提供aCD40和TLR*信号才能限制肿瘤特异性aTreg的出现，这可能是保护性肿瘤免疫发展的关键。将确定控制肿瘤特异性aTreg分化的细胞因子、细胞和分子，并研究aTreg发育如何影响有效肿瘤免疫的机制（Specific Aim #2）。总之，特异性目标#1和#2应该提供如何利用aCD407TLR*平台最大化免疫效应机制和限制对肿瘤特异性抗原的免疫调节的机制理解。增强免疫效应机制和抑制免疫调节可能由一个涉及Treg、IL-9和肥大细胞的新的细胞回路控制。我们的研究表明，肥大细胞是CD4+CD25+Foxp3+ treg依赖性外周耐受的重要中介。与肥大细胞的促炎作用相反，我们报道肥大细胞在介导外周抑制中起关键作用。激活Treg产生的高水平IL-9（肥大细胞生长因子）在耐受组织肥大细胞募集和激活中是重要的。IL-9是激活Treg招募和激活肥大细胞介导区域化免疫抑制的功能纽带。我们提供的数据表明Treg、肥大细胞和IL-9也在下调肿瘤免疫反应中发挥作用。我们假设有效的免疫干预将影响Treg - il -9肥大细胞轴，从而导致保护性肿瘤免疫（Specific Aim #3）。了解如何将这种新型佐剂平台应用于临床，用于制造有效的肿瘤疫苗，将为诱导对癌症的免疫提供新的途径。

DESCRIPTION (provided by applicant): The combined use of TLR and CD40 agonists together with tumor antigen is a novel vaccine platform that elicits robust immunity resulting in the effective eradication of pre-existing cancer. The synergy that is manifested by the combined administration of both CD40 and TLR agonists (TLR*) is represented by an greatly enhanced frequency of atumor effector T cells. Maximizing this approach to provide improved therapeutic protection in cancer, understanding the mechanisms underlying the generation of tumor-specific effector T cells and the testing of this vaccine platform approach in multiple, clinically-relevant models of melanoma will be sought (Specific Aim#1). While understanding how an effective cancer vaccine can elicit potent atumor effector T cells is important, it is equally important to resolve how it limits the emergence of regulatory T cells (Treg). Ample evidence establishes that natural (n)Treg and adaptive (a)Treg can dramatically influence the immune responses to tumor. Our data shows that only when both aCD40 and TLR* signals are provided can one limit the emergence of tumor-specific aTreg, and this may be key to the development of protective atumor immunity. Cytokines, cells and molecules that control the differentiation of tumor-specific aTreg will be identified and the mechanisms of how aTreg development influences effective atumor immunity will be studied (Specific Aim #2). Together, Specific Aims #1 and #2 should provide a mechanistic understanding of how to maximize immune effector mechanisms and limit immune regulation to tumor-specific antigens using the aCD407TLR* platform. Enhancing immune effector mechanisms and dampening immune regulation may be controlled by a new cellular circuitry involving Treg, IL-9 and mast cells. Our studies show that mast cells are essential intermediaries in CD4+CD25+Foxp3+ Treg-dependent peripheral tolerance. Contrary to the pro-inflammatory role played by mast cells, we have reported that mast cells are critical in mediating peripheral suppression. High levels of IL-9 (mast cell growth factor) produced by activated Treg is important in mast cell recruitment and activation in tolerant tissue. IL-9 represents the functional link through which activated Treg recruit and activate mast cells to mediate regionalized immune suppression. We present data that Treg, mast cells and IL-9 also play a role in down- regulating the immune response to tumors. We hypothesize that effective immune intervention will impact on the Treg -IL-9-mast cell axis leading to protective tumor immunity (Specific Aim #3). Developing an understanding of how to implement and deliver this novel adjuvant platform into the clinic for use in the creation of an effective atumor vaccine will provide new avenues for the inducing immunity to cancers.